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Molecular Pharmacology, Vol 12, 1091-1105, Copyright © 1976 by the American Society for Pharmacology and Experimental Therapeutics

Ligand Interactions with Cholinergic Receptor-Enriched Membranes from Torpedo: Influence of Agonist Exposure on Receptor Properties

GREGORY WEILAND 1, BRIAN GEORGIA 1, VICTORIO T. WEE 1, COLIN F. CHIGNELL 1, and PALMER TAYLOR 1

1 Division of Pharmacology, Department of Medicine, University of California, San Diego, La Jolla, California 92093, and Section on Molecular Pharmacology, National Heart and Lung Institute, National Institutes of Health, Bethesda, Maryland 20014

Carbamylcholine and a nitrogen-substituted mononitroxide congener of decamethonium (I) show an inhibitory capacity toward the binding of cobra agr-toxin to membranes enriched in cholinergic receptor that is dependent on the duration of exposure of the quaternary ligand prior to adding toxin. This behavior is characterized by (a) inhibition of the initial rate of toxin binding, which depends on the duration of ligand conditioning, (b) depression of the equilibrium binding of toxin, which at short exposure intervals cannot be accounted for by the decrease in association rate for toxin binding, and (c) a slow change in receptor state, in which the affinity for ligand is increased. The last can be demonstrated directly by electron spin resonance measurements of the free and bound resonance peaks of the spin-labeled bisquaternary ligand. The slow increase in affinity measured by ESR appears to be slightly smaller than the increased affinity calculated from conditioning effects of ligand exposure on the initial rate of toxin binding. The spin-labeled ligand is completely dissociated by excess toxin and binds to one site per toxin binding site. Conditioning effects of the ligands are lost upon solubilization of the receptor with Triton X-100. In contrast to the above ligands, the antagonist d-tubocurarine does not show time-dependent inhibition of toxin binding, and its interaction with the receptor-enriched membranes appears to be competitive with toxin binding.

Submitted on April 12, 1976
Accepted on July 6, 1976




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